Abstract: Dental caries is the local destruction of hard tooth tissue caused by acidic byproducts generated by cariogenic bacteria, primarily Streptococcus mutans, which ferment free sugars in the presence of host factors, dietary components, and environmental conditions. A main feature of dental caries is the formation of dental plaque biofilm, which significantly improves the resistance of bacteria to drugs and host immunity. Traditional anti-caries drugs mainly exert anti-biofilm functions indirectly through antibacterial activities. However, they tend to interfere with the symbiotic microbiota while inhibiting cariogenic bacteria, which may cause imbalance within the oral microbial system. With increasing attention paid to the homeostasis of oral microbiota, new types of anti-caries drugs have been developed, such as natural extracts, artificially synthesized small molecules, and oligonucleotides. They act on key targets to inhibit the formation of biofilm substrates or regulate the interactions between oral microorganisms, thereby efficiently inhibiting biofilm formation. These drugs do not have bactericidal effects. Nevertheless, they exert indirect antimicrobial effects by interfering with biofilm substrate formation or microbial interactions. The optimization of delivery carriers, combination drug therapy, and biomimetic design further enhance the efficacy of these new types of anti-caries drugs. This article provides a review of the prevention and treatment principles and key targets of dental plaque biofilm. We also discussed the types, mechanisms of action, and development trends of relevant drugs.